Letters
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 6 1321
Refer en ces
(1) Tsuruma, T.; Yagihashi, A.; Hirata, K.; Matsuno, T.; Zou, X. M.;
Sasaki, K.; Asanuma, K.; Endo, T. Evaluation of plasma IL-8
(CINC) concentration during ischemia and after reperfusion in
the small intestine. Transplant. Proc. 1996, 28 (3), 1917-1918.
Frieri, M.; Therattil, J . M.; Zitt, M.; Bouboulis, D.; Wang, S. F.;
Lark, G.; Schaefer, P. A.; Sansone, G. Allergen-stimulated
leukotriene B4 and interleukin-8 levels in patients with asthma
and allergic rhinitis-modulation by a lipid pathway inhibitor.
Ann. Allergy, Asthma, Immunol. 1998, 81 (4), 331-336. Takaya-
ma, F.; Miyazaki, T.; Aoyama, I.; Tsukushi, S.; Sato, M.;
Yamazaki, C.; Shimokata, K.; Niwa, T. Involvement of inter-
leukin-8 in dialysis-related arthritis. Kidney Int. 1998, 53 (4),
1007-1013. Hay, D. W. P.; Sarau, H. M. Interleukin-8 Receptor
Antagonists in Pulmonary Diseases. Curr. Opin. Pharmacol.
2001, 1, 242-247. Bizzarri, C.; Allegretti, M.; Di Bitondo, R.;
Neve Cervellera, M.; Colotta, F.; Bertini, R. Pharmacological
inhibition of interleukin-8 (CXCL8) as a new approach for the
prevention and treatment of several human diseases. Curr. Med.
Chem.: Anti-Inflammatory Anti-Allergy Agents 2003, 2,
67-79.
(2) Murphy, P. M.; Tiffany, H. L. Cloning of complementary DNA
encoding a functional human interleukin receptor. Science 1991,
253, 1280-1283. Holmes, W. E.; Lee, J .; Kuang, W. J .; Rice, G.
C.; Wood, W. I. Structure and functional expression of a human
interleukin-8 receptor. Science 1991, 253, 1278-1280. Walz, A.;
Burgener, R.; Car, B.; Baggiolini, M.; Kunkel, S. L.; Strieter, R.
M. Structure and Neutrophil-Activating Properties of a Novel
Inflammatory Peptide (ENA-78) with Homology to Interleukin-
8. J . Exp. Med. 1991, 174, 1355-1362. Wolf, M.; Delgado, M.
B.; J ones, S. A.; Dewald, B.; Clark-Lewis, I.; Baggiolini, M.
Granulocyte chemotactic protein 2 act via both IL-8 receptors,
CXCR1 and CXCR2. Eur. J . Immunol. 1998, 28, 164-170.
(3) Cacalano, G.; Lee, J .; Kikly, K.; Ryan, A.; Pitts-Meek, S.;
F igu r e 2. Shild plot for 1f in GROR-induced calcium mobi-
lization assay. Data were plotted from eight separate GROR-
induced calcium mobilization experiments using varying con-
centrations of GROR with eight fixed concentrations of
antagonist.
intravenously co-infused with IL-8, the compound com-
pletely blocked the IL-8-induced neutropenia (Figure 1).
These phenolic ureas are cleared rapidly in vivo prob-
ably because of glucuronidation and/or sulfation of the
phenol.8 Since the compounds are rapidly cleared, their
efficacy was evaluated in a topical model of delayed-
type hypersensitivity (DTH) where IL-8 has been im-
plicated to mediate the response.9 In a rabbit model of
DTH, the inflammatory response was induced by intra-
dermal injection of tuberculin in animals that had
previously been sensitized with complete Freund’s
adjuvant. Of the four compounds tested in this model
(Table 1), ureas 1e and 1f both demonstrated significant
inhibition (31% and 33%, respectively) at a dose of 500
µg of test compound per injection site.
Con clu sion . In summary, our SAR investigation
with the phenolic urea series of CXCR2 antagonists has
led to the identification of 1f, a potent and selective
agent active both in vitro and in vivo. The activities
found with the selective CXCR2 antagonist 1f indicate
that the CXCR2, as opposed to the CXCR1, is more
important for neutrophil chemotaxis and recruitment.
Ongoing studies with this series of compounds should
provide important new information on the roles of
CXCR1 and CXCR2 in inflammatory processes.
Hultgren, B.; Wood, I.; Moore, W. Neutrophil and
B Cell
Expansion in Mice That Lack the Murine IL-8 Receptor Ho-
molog. Science 1994, 265, 682-657.
(4) For other classes of CXCR2 antagonists, see the following.
Baxter, A.; Bennion, C.; Bent, J .; Boden, K.; Brough, S.; Cooper,
A.; Kinchin, E.; Kindon, N.; McInally, T.; Mortimore, M.; Roberts,
B.; Unitt, J . Hit-to-lead studies: The discovery of potent, orally
bioavailable triazolethiol CXCR2 receptor antagonists. Bioorg.
Med. Chem. Lett. 2003, 13, 2625-28. Li, J . J . Small Molecule
Interleukin-8 Modulators. Expert Opin. Ther. Pat. 2001, 11,
1905-1910.
(5) White, J . R.; Lee, J . M.; Young, P. R.; Hertzberg, R. P.; J urewicz,
A. J .; Chaikin, M. A.; Widdowson, K.; Foley, J . J .; Martin, L. D.;
Griswold, D. E.; Sarau, H. M. Identification of a Potent, Selective
Non-Peptide Antagonist That Inhibits Interleukin-8-Induced
Neutrophil Migration. J . Biol. Chem. 1998, 273, 10095-
10098.
(6) Widdowson, K.: Veber, D. F.; J urewicz, A. J .; Nie, H.; Hertzberg,
R. P.; Holl, W.; Sarau, H. M.; Foley, J . J .; Lee, J . M.; White, J .
R. Peptides 1996; Ramage, R., Ed.; Mayflower Scientific Ltd.,
1998; pp 87-92.
(7) Widdowson, K.; Nie, H.; J urewicz, A. J .; Hertzberg, R. P.; Sarau,
H. M.; Foley, J . J .; Lee, J .; White, J . R.; Veber, D. F. The role of
the anionic groups in the receptor binding of interleukin-8
antagonists. Lett. Pept. Sci. 1998, 5, 235-239.
(8) Silverman, R. B. The Organic Chemistry of Drug Design and
Drug Action; Academic Press: New York, 1992.
(9) Larsen, C. G.; Thomsen, M. K.; Gesser, B.; Thomsen, P. D.;
Deleuran, B. W.; Nowak, J .; Skodt, V.; Thomsen, H. K.; Deleu-
ran, M.; Testrup-Pedersen, K.; Harada, A.; Matsushima, K.;
Meene, T. The delayed-type hypersensitivity reaction is depend-
ent on IL-8: Inhibition of a tuberculin skin reaction by an anti-
IL-8 antibody. J . Immunol. 1995, 155, 2151-2157.
Ack n ow led gm en t. The authors thank Dr. J akob
Busch-Petersen and Qi J in, both of GlaxoSmithKline,
for their assistance in preparing this manuscript.
(10) Kraft, A. S.; Anderson, W. B. Nature 1983, 301, 621-623.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of ureas 1a -h . This material is
J M034248L